The invention relates to compounds and methods for changing calcium metabolism within the cells of a mammal.
Calcium ions appear to play an important role in innumerable physiological body functions in mammals. Thus, calcium ions are involved in blood clotting and coagulation, cellular adhesion, integrity and membrane stability, bone and teeth formation, enzyme activity, control of certain aspects of cyclic nucleotide metabolism, mediation of certain activities of prostaglandins, cell division, muscle contraction, glandular and other cellular secretory functions, neuronal transmission and numerous other physiological functions. Calcium also effects the pharmacological and toxicological actions of many drugs and chemicals. Accordingly, it is not surprising that the pharmaceutical efficacy of many drugs is dependent at least in part upon their calcium antagonist activity, although in most cases it has only recently been recognized that it is the calcium antagonist activity of the drug which is responsible for its pharmaceutical activity. Such drugs include local anesthetics, anticonvulsants, antiarrhythmics, coronary dilators, antihypertensives and skeletal muscle relaxants as well as other types of drugs.
The calcium required for the aforementioned physiological functions may be derived from either extracellular sources (basement membrane, ground substance or extracellular fluids) or intracellular calcium storage pools (mitochondria, endoplasmic reticulum, nucleus, the inner aspect of the plasma membrane and possibly secretory vesicles). Calcium antagonist drugs may operate either by affecting the rate at which calcium is transported into the cell from extracellular sources or by affecting the metabolism of intracellular calcium (by inhibiting the action or mobilization of intracellular calcium, by enhancing the sequestration of calcium ion by intracellular organelles or by altering its rate of efflux from the cell). The former group of calcium antagonist drugs are known as calcium entry blockers and include local anthestics, manganese, lanthanum, phenytoin, barbiturates, Org 6001 (3.alpha.-amino-2.beta.-hydroxy-5.alpha.-androstan-17-one), methadone, 1-acetylmethadol, 1-pentazocine, dantrolene, nitroglycerine and other nitrites and organic nitrates, indomethacin, adrenergic .beta..sub.2 -receptor agonists, morphine, alcohol, aminoglycoside antibiotics such as streptomycin and neomycin, SKF-525A, R33711, flunarizine, cinnarizine, hydralazine, lidoflazine, bepridil, cinepazet maleate, hexoestrol and the prenylamine group of compounds including prenylamine itself, verapamil, methoxyverapamil (D600), fendiline, nifedipine, ditiazem, perhexiline and FR 7534. The physiological action of most of the calcium entry blockers is complicated by the fact that they also block the entry of sodium into the cell and this can make their activity difficult to predict.
The other main group of calcium antagonists which act on intracellular calcium are known as intracellular calcium antagonists and include magnesium, sodium nitroprusside, diazoxide, dantrolene, ryanodine, and the .omega.-(N,N-diethylamino) alkyl-3,4,5-trimethoxybenzoates.
We have previously synthesized 2-alkyl-5,6-methylenedioxyindene-1-dimethylammonium salts wherein the 2-substituent is an n-propyl or n-butyl group. Although these compounds were obtained as intermediates in the synthesis of potential prostaglandin antagonistic end products, screening of the compounds for potential prostaglandin receptor antagonistic activity of isolated rat uteri showed that these compounds were not selective prostaglandin blockers but indicated that they appear to be calcium antagonists. Our further work on these compounds has indicated that they are indeed intracellular calcium antagonists. In particular, we have shown that these two compounds inhibit rodent nonvascular smooth muscle contraction, bovine coronary vessel constriction and bovine adrenomedullary catecholamine secretion. The compounds have also been shown to increase coronary flow and decrease cardiac inotropic activity in isolated rabbit heart preparations. Moreover, the compounds have been shown to have significant antiarrhythmic activity against ouabain-arrhythmias in dogs, and our further work shows them to be effective against calcium-induced arrhythmias in dogs and rats, aconitine-induced and methacoline-induced arrhythmias in rats and chloroform/anoxia-induced arrhythmias in mice. This further work of ours shows that in the calcium-induced arrhythmia model in rats, both the propyl and butyl compounds were more potent and safer than verapamil, which is one of the standard drugs used in this field. In the chloroform/anoxia-induced arrhythmia model in mice, the butyl compound was more potent than quinidine and the propyl compound was as potent as quinidine. Earlier published work of ours has shown both the propyl and the butyl compounds show a remarkable lack of toxicity when tested acutely and subchronically.
The synthesis and physiological activity of the aforementioned dimethylaminoindenes are described in the following papers:
I. D. T. Witiak, D. R. Williams, S. V. Kakodkar, G. Hite and M. S. Chen, J. Org. Chem., 39, 1242 (1974).
II. R. G. Rahwan, M. M. Faust and D. T. Witiak, J. Pharmacol. Exp. Ther., 201, 126 (1977).
III. M. F. Piascik, R. G. Rahwan and D. T. Witiak, J. Pharmacol. Exp. Ther., 205, 155 (1978).
IV. D. T. Witiak, S. V. Kakodkar, T. P. Johnson, J. R. Baldwin and R. G. Rahwan, J. Med. Chem., 22, 77 (1979).
V. C. E. Akesson, R. G. Rahwan, D. T. Witiak, R. J. Brumbaugh, Res. Commun. Chem. Pathol. Pharmacol. 27, 265, (1980).
VI. R. G. Rahwan, M. F. Piascik, D. T. Witiak, Canad. J. Physiol. Pharmacol, 57, 433, (1979).
VII. M. F. Piascik, R. G. Rahwan and D. T. Witiak, J. Pharmacol. Exp. Ther., 210, 141 (1979).
VIII. M. F. Piascik, M. T. Piascik, D. T. Witiak and R. G. Rahwan, i Canad. J. Physiol. Pharmacol., 57, 1350 (1979); and
IX. R. G. Rahwan, C. E. Akesson and D. T. Witiak, Res. Commun. Chem. Pathol. Pharmacol. 26, 85 (1979).
We have now synthesized derivatives of the aforementioned propyl and butyl aminoindenes and related compounds. Certain of these new derivatives exert a more powerful pharmacological activity than the aforementioned aminoindenes from which they are derived.